A neuron is comprised of a nucleus within a body, or soma, a long fiber called the axon, and a varying number of branching fibers called dendrites, which extend out to other neurons. In recent years, a number of nuclear factors have been localized in the cytoplasm of neurons. Indeed, several nuclear transcription factors, such as Elk-1 (Sgambato et al., 1998, The Journal of Neuroscience 18: 214-226), ATF4 (Vernon et al., 2001, Molecular and Cellular Neuroscience 17: 637-645), NFκB (Lerner-Natoli et al., 2000, Epilepsy Research 41: 141-154) IκB (Yoshiyama et al., 2001, NeuroReport 12: 2641-2645) and CREB (Crino et al., 1998, Proc. Natl. Acad. Sci. USA 95: 2313-2318) have all been found in dendrites.
Elk-1 belongs to the ETS domain transcription factor family and the ternary complex factor (TCF) subfamily (Sharrocks et al., 2002, Biochemical Society Transactions 30:1-9). The deletion of Elk-1's DNA binding domain has been shown to eliminate Elk-1 DNA binding and subsequent Elk-1 transcriptional activity (Janknecht and Nordheim, 1992, Nuc. Acids Res. 20:3317-3324). In the nucleus, Elk-1 forms a ternary complex with the serum response factor (SRF) protein and the serum response element (SRE) promoter region. In addition to an N-terminal DNA binding domain, Elk-1 contains a “B box” mediating its interaction with SRF, a “C domain” acting as a transcriptional activation domain, two repression domains, and two domains which act as docking sites for multiple MAP kinases including ERK and JNK (Sharrocks et al., 2002, Biochemical Society Transactions 30:1-9). Activation of Elk-1 in the nucleus by phosphorylation is thought to impact neuronal differentiation (Sharrocks et al., 2001, Nature Reviews Molecular Cell Biology 2: 827-837), cell proliferation (Sharrocks et al., 2002, Biochemical Society Transactions 30:1-9), tumorigenesis (Chai et al., 2001, Oncogene 20: 1357-1367) and apoptosis (Sharrocks et al., 2002, Biochemical Society Transactions 30:1-9). Further, Elk-1 phosphorylation has been shown to be upregulated in response to the induction of both long-term depression (LTD) and long-term potentiation (LTP) in the hippocampus in vivo, suggesting a potential role for Elk-1 in synaptic plasticity (Thiels et al., 2002, The Journal of Neuroscience 22: 2054-2062; Davis et al., 2000, The Journal of Neuroscience 20: 4563-4572).
To date, the role or functional consequence of Elk-1 localization in dendrites has not been elucidated. An understanding of the role or function of a nuclear transcription factor localized in dendrites of a neuron would contribute to the understanding of regulation, metabolism and growth of neurons, and thus to more accurate and more useful control and manipulation of neurons. The development of such tools will enable precise, targeted therapies and treatments of all mammals, and in particular, of humans. Therefore, there exists a need for a better understanding of the function and role of Elk-1 in the cytoplasm of neurons in order to facilitate the controlled manipulation of cells. Further, there is a need in the art, satisfied by the present invention, to be able to modulate Elk-1 expression in a cell and thereby provide therapy to an individual having a neurodegenerative disease. The present invention addresses and meets these needs.